2,4,6,7-tetra substituted quinazolines



United States Patent 3,511,836 2,4,6,7-TETRA SUBSTITUTED QUINAZOLINESHans-Jurgen E. Hess, Groton, Conn., assignor to Chas. Pfizer & Co.,Inc., New York, N.Y., a corporation of Delaware No Drawing.Continuation-impart of application Ser. No. 555,704, June 7, 1966. Thisapplication Dec. 13, 1967, Ser. No. 690,101

Int. Cl. C07d 51/48 U.S. Cl. 260256.4 7 Claims ABSTRACT OF THEDISCLOSURE Novel 2,4-diaminoquinazolines wherein at least one of the 6-or 7-positions is substituted with alkoxy having from 1 to 3 carbonatoms and acid addition salts thereof, the preparation thereof and theutility thereof as hypotensive agents.

CROSS REFERENCE TO RELATED APPLICATIONS This application is acontinuation-in-part of application Ser. No. 555,704, filed June 7,1966, and now abandoned, which, in turn, is a continuation-in-part ofapplication Ser. No. 469,879, filed Aug. 6, 1965, and now abandoned.

BACKGROUND OF THE INVENTION This invention relates to new and usefulcompounds which are valuable therapeutic agents. More particularly, itis the object of this invention to provide new and usefulchemotherapeutic agents valuable in reducing blood pressure inhypertensive subjects.

SUMMARY OF THE INVENTION In accordance with the present invention,compounds found to have valuable hypotensive properties are those of theformulae:

R R R and R are each selected from hydrogen, alkyl having from 1 to 5carbon atoms, alkenyl having from 3 to 5 carbon atoms, hydroxyalkylhaving from 2 to 5 carbon atoms, phenyl, benzyl, phenylethyl, Z-furfuryland cycloalkyl where alkyl has from 3 to 8 carbon atoms;

is selected from morpholino, l-azacycloheptyl, l-azacyclooctyl andacetylamino of the formula:

Brill-CH,

where R is hydrogen, acetyl, alkyl having from 1 to 5 carbon atoms andalkenyl having from 3 to 5 carbon atoms; and

3,511,836 Patented May 12, 1970 piperazino of the formula:

where Y is hydrogen, alkyl having from 1 to 5 carbon atoms, hydroxyalkylwhere alkyl has from 2 to 5 carbon atoms, alkanoyl having from 2 to 7carbon atoms, allyl, propargyl, 2-methylallyl, phenyl, benzyl, benzoyl,halobenzoyl and halophenyl where halo is chloro or bromo,trifluoromethyl, methoxyphenyl, methylphenyl, methylbenzoyl,trifluoromethylbenzoyl, furoyl, benzofuroyl, thenoyl, pyridinecarbonyl,3,4,5 trimethoxybenzoyl, carboxylic acid alkyl ester where alkyl hasfrom 1 to 6 carbon atoms, carboxylic acid alkenyl ester where alkenylhas from 3 to 6 carbon atoms; and

piperidino of the formula:

where X is hydrogen, alkyl having from 1 to 5 carbon atoms, alkoxyhaving from 1 to 4 carbon atoms, hydroxy, hydroxyalkyl where alkyl hasfrom 2 to 5 car bon atoms, phenyl, benzyl, 4-phenyl-4-Carboxylic acidalkyl ester where alkyl has from 1 to 6 carbon atoms;

R and R are each selected from hydrogen and alkoxy having from 1 to 3carbon atoms, at least one of R and R being alkoxy; and the acidaddition salts thereof.

Included in the compounds of this invention areZ-dimethylamino-4-amino-6,7-dimethoxyquinazoline,

2- [4- (Z-furoyl) -1-piperazine-1-yl] -4-a.mino-6',7-

dimethoxyquinazoline,

2-(4-allyl-1-piperazinyl) -4-amino-6,7-dimethoxyquinazoline,

2- [4- (Z-methylallyl) l-piperazinyl] -4-amino-6,7-

dimethoxyquinazoline, and

2- (4-benzoyll-piperazinyl) -4-amino-6,7-dimethoxyqu'mazoline.

Of the preceding compounds, 2-dimethylamino-4-amino-6,7-dimethoxyquinazoline dihydrochloride has been tested andreported by J. D. Thayer et al. in Antibiotics and Chemotherapy, vol.II, No. 9, September 1952, p. 463-466, as an antibacterial agent andfound to have a slight order of activity. Furthermore, U.S. Pat. No.2,945,859, issued on July 19, 1960, to George H. Hitchings et al.,discloses 2,4-diamino 6,7 -dimethy1- quinazoline as an antibacterialagent. However, it is the existence of these compounds in the aforesaidprior art which necessitates my excluding them and their isomers andhomologues, from the compound claims of this invention.

I have also discovered that another group of known compounds havevaluable hypotensive activity. These compounds have the structure ofFormula I where R and R are hydrogen or alkyl having from 1 to 3 carbonatoms; R and R are hydrogen, alkyl having from 1 to 3 carbon atoms, atleast one of R and R is dimethylaminoalkyl, diethylaminoalkyl,dipropylaminoalkyl, methylaminoalkyl, ethylaminoalkyl orpropylaminoalkyl where alkyl has from 2 to 4 carbon atoms. Homologuesand positional isomers of these compounds are disclosed by Chapman,Gibson and Mann, J. Chem. Soc., 895-898 (1947), and Curd, Ho-ggarth,Landquist and Rose, J. Chem. 500., 17661773 (194-8).

DETAILED DESCRIPTION OF THE INVENTION The compounds of this inventionare particularly effective in reducing blood pressure in hypertensivesubjects. On tests with renal hypertensive dogs, as little as 0.06 mg.of active ingredient per kilogram of body weight was found effective inreducing blood pressure from 180/100 to 160/100 mm. Hg. The results ofthese tests are shown in the examples below. These compounds areprepared by the cyclization of ureido derivatives of various aromaticacids, amides, nitriles and esters with aqueout base or acid. The ureidoderivatives are obtained by reacting the aromatic compound with sodiumor potassium cyanate or by reacting the aromatic acid with ureaaccording to the procedure of HRS. Curd, et al in the Journal of theChemical Society (London) 1947, p. 777.

After cyclization, the resulting 2,4-dihyclroxyquinazoline ischlorinated at the 2 and 4 positions with a mixture of phosphoruspentachloride and phosphoryl chloride or with a mixture of phosphorylchloride in N,N- dimethylaniline. The preparation of2,4-dichloro-6,7-dimethoxyquinazoline from 4,5-dimethoxyanthranilic acidis shown in the following sequence:

omo- NH2 1) NEOCEN orno 6-011 i 2 1101 i N 01130 OOH 011,0

t on

g N 01130 =0 Pom/Pom CH rcr N-H N 01130 omo H l o 01 The substituents atthe 5,6,7- and 8 positions of quinazoline are controlled to a greatextent by the substituents on the starting aromatic acid, amide,nitrile, or ester. Exceptions such as preparing a S-aminoquinazoline byreducing S-nitroquinazoline prepared from 6- nitroanthranilic acid areobvious to one skilled in the art. Typical 2,4-dichloroquinazolines,obtained by cyclization and chlorination, and their starting compoundsare given in Table I.

TABLE I Substituted 2,4-dichloroquinazolines Starting compounds:Substituent .S-methoxyanthranilic acid 6-methoxy-4-mcthoxyanthranilamide 7-methoxymethyl 4-methoxyanthranilate 7-methoxy-4-methoxyanthranilic acid 7-methoxy- 4-amy1oxyanthranilic acid7-amyloxy- S-amyloxyanthranilic acid 6-amloxy- -6-aminoveratric acid6,7-dimethoxy- 4,5-diamyloxyanthranilic acid 6,7-diarnyloxy-S-methylanthranilic acid -6-methyl- 4-methylanthranilic acid 7-methyl-4-ethylanthranilic acid 7-ethyl- 4-n-propylanthranilic acid 7-n-propyl-4-isopropylanthranilic acid 7-isopropyl- S-n-proplanthranilic acid6-n-propyl- 4,5-dimethylanthranilic acid 6,7-dimethyl-4,5-di-n-propylanthranilic acid 6,7-di-n-propyl- The process employedfor preparing the novel compounds of this invention involves treatingthe corresponding 2,4-dichloroquinazoline with the appropriate aminebase. The 2-chloro-4-aminoquinazolines are prepared by reactingequimolar quantities of ammonia in tetrahydrofuran and2,4-dichloroquinazoline. However, in ordinary practice a preferredexcess of ammonia would be from one to ten moles in order to shift thereaction to completion. Higher amines and nitrogenous heterocycliccompounds are likewise reacted with the dichloro compound to yield2-chloro-4-substituted-quinazolines. The temperature at which thisreaction can be conducted varies from 25 to about 200 C. for a period offrom one to 48 hours. A preferred reaction temperature and time for thisreaction would be about 25-60 C. for about four hours. Upon completionof reaction the product is recovered by conventional means. Forinstance, the solvent can be evaporated and the crude solid can betriturated with water or precipitated from dilute aqueous acid incrystalline form and subsequently recrystallized from any number ofappropriate organic solvents such as methanol o-r dimethylformamide.

Replacement of chlorine in the 2-position of the quinazoline nucleus isaccomplished by reaction of the 2- chloro-4-aminoquinazoline or2-chloro-4-substituted quinazoline with an amino compound such aspiperidine in an aqueous or an organic sol-vent. A molar excess of baseis generally employed, while preferred organic solvents for thesepurposes include polar solvents like tetrahydrofuran, dioxane,dimethylacetamide, dimethylforrnamide, or alcohols such as methanol,ethanol, and isoamyl alcohol. The reaction mixture is heated from 10 0'to 160 C. for from 1 to 65 hours in a sealed pressure bottle. Apreferred time and temperature is C. and 4 hours for an alkylamine orheterocyclic compound and C. for 65 hours for ammonia in ethanol. Afterthe reaction is complete, the solvent is evaporated and the product isrecrystallized from a mixture of an organic solvent and water. Forinstance, methanol/water. The reaction is illustrated by the followingsteps:

02in oH3o ci (CmmNH oH,o- -N l l I I czrn (EH30 N Ethanol 01130 N l 1L... L,

The well known procedures for preparing salts of basic compounds arealso applicable for the compounds of this invention and are illustratedin the examples below. Such salts may be formed with bothpharmaceutically-acceptable and pharmaceutically-unacceptable acids. Bypharmaceutically-acceptable is meant those saltforming acids which donot substantially increase the toxicity of the basic compound. Thepreferred salts are the acid addition salts. These salts are ofparticular value in therapy. They include salts of mineral acids such ashydrochloric, hydriodic, hydrobromic, phosphoric, metaphosphoric,nitric, and sulfuric acids, as well as salts of organic acids such astartaric, acetic, citric, malic, benzoic, glycollic, gluconic, gulonic,succinic, arylsulfonic, e.g., para-toluenesulfonic acids, and the like.

The pharmaceutically-unacceptable acid addition salts, While not usefulfor therapy, are valuable for isolation and purification of the newlyrecognized biologicallyactive compounds. Furthermore, they are usefulfor the preparation of the pharmaceutically-acceptable salts. Of thisgroup, the more common salts include those formed with hydrofluoric andperchloric acids. Hydrofluoride salts are particularly useful for thepreparation of the pharmaceutically-acceptable salts, e.g., thehydrochloride, by solution in hydrochloric acid and crystallization ofthe hydrochloride salt formed. The perchloric acid salts are useful forpurification and crystallization of the new compounds.

While the procedures described above are preferred for preparing thecompounds of this invention on the l-Cl N LO] basis of improved yields,alternate methods may also be used. The alternate methods may be dividedinto eight groups for convenience:

1) Halogenation of a substituted -3(4)-dihydroquinazoline-4-one to yieldsubstituted-4-haloquinazolines, followed by reaction with anitrogen-containing compound at position 4.

(2) Thiolation of a substituted -(1H,3H)-quinazoline- 2,4-dione with orwithout subsequent alkylation and reaction with a nitrogen-containingcompound.

(3) Alkylation, alkanoylation, aroylation and alkoxylation of piperazineattached to position 2 or 4 of the quinazoline nucleus.

(4) Reaction of guanidine with 2-amino-4,5-dissubstituted benzonitrilesto form substituted quinazolines.

(5) Reaction of guanidines with 2-chloro-4,5-disubstituted-benzonitrilesto form Z-substituted amino-4- amino-6,7-disubstituted-quinazolines.

(6) Reaction of guanidines with 2-amidino-4,5-disubstituted-anilines toform 2-substituted-amino-4-amino-6,7- disubstituted-quinazolines.

(7) Reaction of 2-chloro-4-a1koxy-6,7-disubstitutedquinazolines withammonia or amino compounds to form 2-substituted amino 4amino-6,7-disubstituted-quinazolines.

(8) Reaction of 2-chloro-4-methylthio 6,7- disubstituted-quinazolineswith ammonia or amino compounds to form Z-substituted amino 4amino-6,7-disubstituted-quinazolines.

In method (1),4(3H)-quinazolines which are described in previouslycopending application Ser. No. 442,205 filed Mar. 23, 1965 nowabandoned, are halogenated with reagents such as phosphorousoxychloride, phosphorous oxybromide, phosphorus trichloride, phosphorouspentachloride, thionyl chloride or the like, to produce thecorresponding 4-haloquinazoline which is then reacted with an amine orheterocyclic compound according to the procedures previously describedherein. The following sequence illustrates this method:

as previously In this method, a molar equivalent amount, and preferablyan excess, of one of the aforementioned halogenating agents is added tothe 3,4-dihydroquinazoline- 4-one or an acid salt such as thehydrochloride, sulfate, phosphate, hydrobromide or the like. The reagentis added slowly to the quinazoline at room temperature and then themixture is refluxed for from about minutes to about 2 hours. The lattertime is sufficient for sam ples of about 10 grams of the quinazoline. Ofcourse, longer reflux periods are desirable for larger batches in orderto insure complete reaction. The liquids are evaporated and theresulting crystalline residue is then redissolved in a dilute aqueoussolution of sodium bicarbonate, sodium carbonate, sodium hydroxide orthe corresponding potassium salts. The aqueous solution is extractedwith a solvent such as chloroform or ethyl ether. While the specificextractant is not an essential part of the process, chloroform ispreferred on the basis of convenience and safety. The combined extractsare dried with a drying agent such as sodium sulfate, potassiumcarbonate or the like and the solvent is evaporated to yield thequinazoline substituted with chlorine or bro mine on position 4. Theresulting compound is reacted with ammonia, amines or heterocyclics byany of the aforementioned methods.

An alternate procedure involving this method, consists in reacting the4-haloquinazoline with at least a molar equivalent amount of sodiumsulfide, thiourea, thioacetamide or sodium methyl mercaptan. Sodiumsulfide is reacted from an aqueous solution, sodium methyl mercaptan maybe reacted either from aqueous solution or alkanol solution such asmethanol, ethanol, isopropanol or the like. Thiourea and thioacetamideare reacted from alkanol solution and ethanol is most convenient. Thereaction of the 4-haloquinazoline with these sulfur-containing compoundsis accomplished at reflux for from about 2 to 8 hours, depending on thesize of the samples. The reactions proceed according to the following:

where R R and Z are as previously disclosed and where Z may also bewhere R and R are as previously disclosed. The reaction products areallowed to precipitate from the cooled reaction mixture and may berecrystallized from such solvents as ethanol-water mixtures. Therecrystallized and dried products may then be reacted withheterocyclics, ammonia or amines according to the procedures previouslydescribed for reacting the 4-haloquinazolines to obtain nitrogensubstituents on position 4.

In method (2) a substituted quinazoline-2,4-dione is reacted with areagent such as phosphorous pentasulfide or the like to form the2,4-dithioquinazo1ine which in turn is reacted with an alkyl or benzylhalide to form the thioalkyl derivative. The thioalkyl derivative isthen reacted with an amine or a heterocyclic compound by the procedurespreviously described for the reaction of 2,4-dichloroquinazoline to formnitrogen-containing substituents on positions 2 and 4 of the quinazolinenucleus. This method is illustrated by the following sequence:

where R R R R R R and Z are as previously described.

The compounds of this invention are prepared by reacting at least amolar equivalent amount of phosphorous pentasulfide with thequinazoline-2,4-dione and preferably an excess of the pentasulfide toensure complete reaction. While the quinazoline may be dissolved in anynon-reactive solvent, the use of a pyridine'solution is preferred. Thepentasulfide is added to the stirred solution at room temperature andthen refluxed with continual stirring. As in the previous method, thereflux time is dependent on the size of the sample. After refluxing,

the solvent is removed under reduced pressure, the residue is decomposedwith hot water and the solid dithione is filtered from the mixture. Tothe dithione is added a solvent mixture of aqueous base and an alkanol.Bases useful in this method are sodium hydroxide, potassium hydroxide,and the like. Methanol, ethanol, isopropanol and butyl alcohol areuseful in this method and methanol is preferred on the basis of its lowboiling point. To the solution is slowly added with stirring at least atwicemolar equivalent of an alkylating agent selected from alkyliodides, alkyl chlorides, alkyl bromides and the corresponding henzylhalides. On the basis of their ease of removal from their position asalkylmercapto derivatives of quinazoline, methyl and benzyl iodide, arepreferred. The mixture is heated to the boiling point of Water for about2 hours. For large samples and for lower temperatures, the time may beextended. The mixture is cooled and the precipitated product is filteredfrom the mixture. The resulting 2,4-dialkylor2,4-dibenzylmercaptoquinazoline is reacted with ammonia, amines orheterocyclic compounds according to any of the previously describedprocesses for reacting 2,4-dichloroquinazolines, to obtain the compoundsof this invention. These compounds may also be prepared by reacting thedithione directly with ammonia, amines or a heterocyclic nitrogencompound and equivalent yields of product are obtained thereby.

In method (3), compounds of the formulae:

where R R R R R and R are as previously described are reacted with alkylchlorides and alkyl bromides where alkyl has from 1 to 5 carbon atoms,alkanoyl bromides and alkanoyl chlorides where alkanoyl has from 2 to 7carbon atoms, benzoyl chloride, benzoyl bromide, 2-methy1ben'zoylhalides, S-methylbenzoyl halides and 4- methylbenzoyl halides wherehalide is bromide or chloride, Z-furoyl halide and 3-furoyl halide wherehalide is chloride or bromide, 2-thiophenoyl halide and 3-thiophenoylhalide where halide is chloride or bromide, allyl halide and methylallylhalide where halide is bromide or chloride. In the aforesaid reaction,at least a molar equivalent amount of the halide, and preferably anexcess to ensure complete reaction, is added to a solution of thequinazoline in an organic solvent such as a methyl alkyl ketone,saturated aliphalic hydrocarbon or alkanol at room temperature. Thereaction mixture is stirred for at least /4; hour and up to about 5hours, depending, of course, on the size of the sample. While higherreaction times may be used they result in noxious fumes. Lowertemperatures require longer periods of time for the compounds to react.The solid product is filtered from the reaction mixture and the productmay be recrystallized from such solvents as methanol, ethanol,isopropanol, methylene chloride, chloroform, or the like.

In method (4) Z-aminobenzonitriles of the formula:

R5- NH:

Where R and R are as previously disclosed, are reacted with guanidinesof the formulae:

where R R and Z are as previously disclosed. In this method, thebenzonitrile is dissolved in an inert highboiling solvent such asdimethylformamide, dimethyl sulfoxide, ethylene glycol, or the like. Amolar equivalent amount and preferably and excess of the guanidine isadded and the mixture is heated at about C. for from about 4 to 15hours.

While lower temperatures may be employed for longer periods of time,about 12 hours are preferable for 0.1 molar quantities of reactants toensure complete reaction. After heating, the solution is concentrated invacuo to a small volume, water is added, and the mixture is chilled. Thesolids which precipitate are filtered from the mixture andrecrystallized from solvents such as methanol-water, and dried. Thereaction is illustrated as follows:

In methods and (6), the compounds of this invention are prepared byreacting compounds of the formulae:

where R and R are as previously mentioned, with guanidines of theformula:

HN N by the process described for method (4).

In method (7), 2-chloro-4-alkoxy 6,7 disubstitutedquinazolines whosepreparation is described in Curd, Landquist and Rose, 1. Chem. Soc.,1947, pages 775-783, are reacted at reflux with an amino compound inalcohol for several hours to obtain the2-amino-4-alkoxy-6,7-disubstituted-quinazoline. The 4-position is thenreacted with the same or a different amino compound at highertemperatures to obtain substitution on that position. The reactionsequence is as follows:

wherein R R R R R R and Z are as previously mentioned and wherein R ismethyl, ethyl, phenyl or benzyl.

In method (8), 2-chloro-4-alkylthio 6,7 disubstitutedquinazolines arereacted with amino compounds in refluxing alcohol to obtain2-substituted amino-4-substituted amino 6,7 disubstituted-quinazolines.The reaction sequence is as follows:

wherein R R R R R R R and Z are as previously disclosed.

The compounds of this invention are administered to hypertensivesubjects either alone or in combinations withpharmaceutically-acceptable carriers. The proportion of activeingredient to carrier is determined by the solubility and chemicalnature of the compound, chosen route of administration and standardpharmaceutical practice. For example, they are administered in tabletform with such exci-pients as lactose, sodium citrate, calcium carbonateand dicalcium phosphate. Various disintegrants such as starch, alginicacid and certain complex silicates together with lubricating agents suchas magnesium stearate, sodium lauryl sulfate and talc are often used.For oral ad ministration in capsule form, preferred materials arelactose and high molecular weight polyethylene glycols. When aqueoussuspensions are desired, the essential active ingredients are combinedwith emulsifying and/or suspending agents. Diluents such as ethanol,propylene glycol, glycerine and various combinations of diluents areemployed. For parenteral administration, solutions of the activeingredients in combination with other solutes such as glucose or salineare used. Such aqueous solutions should be suitably buffered ifnecessary to render them isotonic.

The dosage required to reduce blood pressure in hypertensive subjectswill be determined by the nature and the extent of the hypertension.Generally, small dosages will be administered initially with a gradualincrease in dosage until the optimum level is determined. It willgenerally be found that when the composition is administered orally,larger quantities of the active ingredient will be required to producethe same level of blood pressure reduction as produced by a smallerquantity administered parenterally. In general, from about 0.02 to 200milligrams of active ingredient per kilogram of body weight administeredin single or multiple dosage units effectively reduces blood pressure inhypertensive subjects. Tablets containing 0.5 to 50 milligrams of activeingredient are particularly useful.

The following examples are given by way of illustration and are not tobe construed as limiting the invention in any way. Many variations ofthe invention are possible within the spirit of the invention.

EXAMPLE I 2-chloro-4-amino6,7-dimethoxyquinazo1ine To 800 ml. of asolution of anhydrous ammonia in tetrahydrofuran at room temperature isadded 30 g. of 2,4-dichloro-6,7-dimethoxyquinazoline [F.H.S. Curd et.al., J. Chem. Soc., p. 1759 (1948)]. The mixture is stirred for 44hours. The precipitate (29 g., M.P. 267268 C.)

11 is filtered and recrystallized from methanol to yield 19 g. of2-chloro-4-amino-6,7-dimethoxyquinazoline, M.P. 302 C. (dec.).

Analysis.Calcd. for C H N O Cl (percent): C, 50.11; H, 4.20; N, 17.53;Cl, 14.79. Found (percent): C, 49.99; H, 4.27; N, 17.52; Cl, 14.82.

EXAMPLE II 2,4-diamino-6,7-dimethoxyquinazoline To a pressure bottle isadded 7.78 g. of 2,4-dichloro-6,7- dimethoxyquinazoline in 100 ml. ofethanolic ammonia. The mixture is heated at 160 C. for 65 hours. Theclear solution is evaporated to dryness and the residue is crystallizedfrom dimethylformamide/water to yield 8.44 g. of product melting at297299 C. This product is dissolved in 400 ml. of hot water. Thesolution is made alkaline with sodium bicarbonate and the resultingprecipitate is filtered, washed with water and dried to yield 6.6 g. of2,4-diamino-6,7-dimethxyquinazoline, M.P. 242-231 C. Recrystallizationfrom water gives a product melting at 244-246 C.

EXAMPLE III 2,4-diamino-6,7-dimethoxyquinazoline dihydrochloride Thedihydrochloride of 2,4-diamin0-6,7-dirnethoxyquinazoline is prepared bydissolving the base in hot ethanol and adding an ethanolic hydrochloricacid solution to precipitate the salt.

In the same manner, acid addition salts are prepared, in lieu ofhydrochloric, acid, sulfuric, nitric, hydriodic, hydrobromic, phosphoricand metaphosphoric acids, as well as salts of organic acids such astartaric, acetic, citric, malic, benzoic, glycollic, gluconic, gulonic,succinic, arylsulfonic, e.g., p-toluenesulfonic acids and the like.

EXAMPLE IV 2,4-di-(N,N-diphenylamino) -6,7-dimethoxyquinalozine To apressure bottle is added 7.78 g. of 2,4-dichloro-6,7-dimethoxyquinazoline in 100 ml. of a 25% solution of diphenylaminein ethanol. The mixture is heated at 160 C. for 65 hours. The clearsolution is evaporated to dryness and the residue is recrystallized fromdimethylformamide/Water to yield the product. The product is dissolvedin 400 ml. of hot water. The solution is made alkaline with sodiumbicarbonate and the resulting precipitate is filtered. washed with waterand dried to yield 2,4-di (N,N-diphenylamino) -6,7-dimethoxyquinazoline.

EXAMPLE V 2-(N,N-dibenzylamino)-4-(N,N-diethylamino) -6,7-

dimethoxyquinazoline To 800 ml. of a solution of diethylamine intetrahy-' drofuran at room temperature is added 30 g. of2,4-dichloro-6,7-dimethoxyquinazoline. The mixture is stirred for 48hours. The precipitate is filtered and recrystallized from methanol. To5 grams of the product is added a solution of dibenzylamine in ethanol.The mixture is heated at 160 C. for 16 hours in a pressure bottle. Thesolvent is evaporated and the product is recrystallized frommethanol/water.

EXAMPLE VI A number of 2,4-disubstituted-amino-6,7-dimethoxyquinazolinesand their pharmaceutically-acceptable acid addition salts are preparedin the same manner as Examples III, IV and V with2,4-dichloro-6,7-dimethoxyquinazoline and the appropriate aminocompound. The products of these reactions are given in Table II.

EXAMPLE VII 2,4-dichloro-6-rnethoxy-7-amyloxyquinazoline To 20 grams of4-amyloxy-5-methoxy anthranilic acid in acetic acid (100' ml.) is addeda suspension of sodium cyanate (11 g.) in water (50 gml.) and stirredwell. After 1 hour, 2-ureido-4-amyloxy5-rnethoxy benzamide is collected,washed and recrystallized from water. Twenty grams of the product isheated with 8 N hydrochloric acid (50 ml.) on a steam bath for 1 hour.The resulting product is stirred with aqueous Sodium hydroxide (50 ml.)to form the sodium salt. The salt is filtered, redissolved in 500 ml.hot water and re-precipitated with acetic acid to give2,4-dihydroxy-6-methoxy-7-amyloxyquinazoline. The product is dried andconverted to 2,4- dichloro-compound by refluxing 10 grams of thedihydroxy material with 16 g. phosphorous pentachloride and 10 ml.phosphoryl chloride for several hours. After removal of the phosphorylchloride, the product is distilled from the flask under reducedpressure.

EXAMPLE VIII 7 2,4-dichloro-6-amyloxy-7-methoxyquinazoline The compoundis prepared from 4-methoxy-5-amyloxyanthranilic acid according to theprocedure of EX- ample VII.

EXAMPLE IX 2,4-dichloro-6,7-diamyloxyquinazoline To 20 grams of4,S-diamyloxyanthranilamide is acetic acid (100 cc.) is added asuspension of 11 g. sodium cyanate in 50 ml. water and stirred well.After 1 hour, 2-ureido-4,5-diamyloxy benzamide is collected, washed andrecrystallized from water. Twenty grams of the product is heated with 8N hydrochloric acid cc.) on a steam bath for 1 hour. The resultingproduct is stirred with 35% sodium hydroxide cc.) to form the sodiumsalt. The salt is filtered, redissolved in 500" cc. hot water andre-precipitated with acetic acid to give 2,4-dihydroxy-6,7-diamyloxyquinazoline. The product is dried and converted to2,4-dichloro-6,7-diamyloxyquinazoline by refluxing 10 grams of dihydroxycompound with 16 g. phosphorous pentachloride and 10 cc. phosphorylchloride for six hours. After removal of the phosphoryl chloride, theproduct is distilled from the flask under reduced pressure.

EXAMPLE X 2,4-dichloro-6,7-diethoxyquinazoline The2,4-dichloro-6,7-diethoxyquinazoline is prepared by the procedure ofExample IX starting with 4,5-diethoxyanthranilamide,4,5-diethoxyanthranilic acid or a lower alkyl ester such as methyl4,5-diethoxyanthranilate.

EXAMPLE XI A series of 2,4disubstitutedamino-6,7-dian'iyloxyquinazolines and their pharmaceutically-acceptableacid addition salts are prepared from2,4-dichloro-6,7-diamyloxyquinazoline by the procedures of Examples III,IV, V and IX. These compounds are listed in Table II.

EXAMPLE XII A series of 2,4-disubstituted amino-6,7-diethoxyquinszolinesand their pharmaceutical]y-acceptable acid addition salts are preparedfrom 2,4-dichloro-6,7-diethoxyquinazoline according to the procedure ofExamples II, III and VI. These compounds are listed in Table II.

S-methoxyanthranilic acid such as methyl S-methoxyanthranilate.

EXAMPLE XIV 2,4-dichloro-7-methoxyquinazoline The 2,4-dichloro 7methoxyquinazoline is prepared from 4 methoxyanthranilarnide, 4methoxyanthranilic acid or a lower alkyl ester of the acid accordingtothe procedure of Example VIII.

EXAMPLEXV 2,4-disubstituted-6-methoxyquinazolines and2,4-disubstituted-7-methoxyquinazolines The substituted 6- and7-methoxyquinazolines and their 14 EXAMPLE XIX 2,4-disubstituted-6-methoxy-7-amyloxyquinazoline The2,4-disubstituted-6-methoxy-7-amyloxyquinazoline and itspharmaceutically-acceptable acid addition salts are prepared by theprocedures of Examples II, III and XVII. These compounds are listed inTable II.

pharmaceutically-acceptable acid addition salts are prepared accordingto the procedures of Examples II, III, XII and XIII. These compounds arelisted in Table II.

EXAMPLE XVI 2,4-dichloro-6- (7 -amyloxyquinazoline The2,4-dichloro-6-amyloxyquinazoline and the2,4-dichloro-7-amyloxyquinazoline and their pharmaceuticallyacceptableacid addition salts are prepared according to the procedure of ExampleVIII from S-amyloxyanthranilamide and 4-amyloxyanthranilamide,respectively, or the corresponding acids and lower alkyl esters.

EXAMPLE XVII 2,4-disubstituted-6- (7 -amyloxyquinazoline The2,4-disubstituted-6-(7)-amyloxyquinazolines and their correspondingpharmaceutically-acceptable acid addition salts are prepared from thecorresponding dichlorocompound according to the procedures of ExamplesII, III and XV. These compounds are listed in Table II.

EXAMPLE XVHI 2,4-dichloro-6-methoxy-7-amyloxyquinazoline The2,4-dich1oro-6-methoxy-7-amyloxyquinazoline is prepared by the procedureof Example VIII with 4-amyloxy-S-methoxyanthranilamide, 4 amyloxy 5methoxyanthranilic acid or its lower alkyl esters.

EXAMPLE XX 2-amino-4-morpholino-6,7-dimethoxyquinazoline To ml. of a 25solution of morpholine in tetrahydrofuran at room temperature is added30 g. 2,4-dichloro-6,7-dimethoxyquinazoline. The mixture is stirred for48 hours. The precipitate is filtered and recrystallized from methanol.To 5 g. of the product is added ml. of ethanolic ammonia. The mixture isheated at C. for 16 hours in a pressure bottle. The solvent isevaporated and the residue is recrystallized from methanol/water.

EXAMPLE XXI The 2-amino-4-substituted 6,7 dimethoxyquinazolines andtheir pharmaceutically-acceptable acid addition salts are prepared from2,4-dichloro-6,7-dimethoxyquinazoline according to the procedures ofExamples XX and III. These compounds are listed in Table HI.

EXAMPLE XXII 2dimethylamino-4-morpholino-6,7-dimethoxyquinazoline oratedand the residue is recrystallized from methanol/ water.

EXAMPLE XXIII The 2,4-disubstituted 6,7 dimethoxyquinazolines and theirpharmaceutically-acceptable acid addition salts are prepared accordingto the procedures ofEXamples III and XXII. These compounds are listed inTable III.

EXAMPLE XXIV Z-amino-4-morpholino-6-methoxy-7-amyloxyquinazoline Thiscompound is prepared from 2,4-dichloro-6-methoxy7-amyloxyquinanzolineaccording to the procedures of Examples VII and XX. The dihydrochloridesalt is prepared from the base compound according to the procedure ofExample III.

EXAMPLE XXV The 2-amino-4-substituted-fi-methoxy 7-amyloxyquinazolinesare prepared according to the procedure of EX- pared according to theprocedure of Example III. These compounds are listed in Table III.

EXAMPLE XXVII The 2,4-disubstituted 6(7)arnyloxyquinazolines and the2-amino-4-substituted 6(7)amyloxyquinazolines are prepared according tothe procedures of Examples XVI, XV and XIX. The dihydrochloride salt isprepared according to the procedure of Example III. These compounds arelisted in Table III.

EXAMPLE XXVIII EXAMPLE XXVI The 2-amino-4-substituted6(7)methoxyquinazolines and the 2,4-disubstituted6(7)methoxyquinazolines are prepared according to the procedures ofExamples XIII, XIV, XXIII and XXI. The dihydrochloride salt is pre- To 5grams of 2-chl0ro-4-amino 6,7-d'unethoxyquinazoline prepared as inExample I, is added 20 grams of a 25% solution of 4-methylpiperazine inethanol. The mixture is heated at 160 C. for 16 hours in a pressurebottle. The solvent is then evaporated and the residue is 75recrystallized from methanol/ water,

1 7 EXAMPLE XXX 2-morpholino-4-(N,N-dibenzylamino)-6,7-diamyloxyquinazoline EXAMPLE XXXI TheZ-substituted 4-amino-6,7-dimethoxyquinazolines are prepared as inExample XXIX. The dihydrochloride salt is prepared according to theprocedure of Example III. These compounds are listed in Table IV. I

18 amyloxyquinazoline. The dihydrochloride salts are prepared as inExample HI. These compounds are listed in Table IV.

EXAMPLE XXXIV The 2,4-disubstituted 6-methoxy 7-amyloxyquinanz0- linesare prepared from 2,4-dichloro-6-methoxy-7-amyloxyquinazoline accordingto the procedure of Example XXX. The pharmaceutically-acceptable acidaddition salts are prepared according to the procedure of Example III.These compounds are listed in Table IV.

EXAMPLE XXXV The 2,4-disubstituted 6(7)methoxyquinazolines are preparedfrom 2,4-dichloro 6-rnethoxyquinazo1ine and2,4-dichloro-7-methoxyquinazolines according to the procedure of ExampleXXX. The pharmaceutically-acceptable acid addition salts are preparedaccording to the procedure of Example III. The compounds are listed inTable IV.

EXAMPLE XXXII The 2,4 disubstituted 6,7 dimethoxyquinazolines wherecarbon 2 is substituted with a heterocyclic nitrogen compound, areprepared as in Example XXX. These 70 compounds are listed in Table IV.

EMMPLE XXXIII The 2,4-disubstituted 6,7-diamyloxyquinazolines areprepared as in Example XXX from 2,4-dichloro-6,7-di- 75 EXAMPLE XXXVI 2-(N ,N-dimethylamino)-4-amino-6,7- dimethoxyquinazoline To 5 grams of2-chloro-4-amino-6,7-dimethoxyquinazoline, prepared according to theprocedure of Example I, is added 50 ml. of a 25% solution ofdimethylamine in ethanol. The mixture is heated for 16 hours at 160 C.in a sealed pressure bottle. The solvent is evaporated and the residueis crystallized from methanol/ water to yield the product. M.P. 219222C.

EXAMPLE XXXVI-I 2-(N,N-dimethylarnino)-4-amino-6,7- dimethoxyquinazolineTo grams of 2-chloro-4-amino-6,7-dimethoxyquinazoline is added 50 ml. ofa solution of diethylamine in ethanol. The mixture is heated for 16hours at 160 C. in a pressure bottle. The solvent is evaporated and theresidue (6.9 g.) is crystallized from methanol/Water to yield 3.3 gramsof product melting at 179l80 C.

Analysis.Calcd. for C H N O (percent): C, 60.85; H, 7.30; N, 20.28.Found (percent): C, 61.07; H, 7.17; N, 20.31.

EXAMPLE XXXVII-I 2-(N,N-diethyla-mino) -4-amino-6,7-dimethoxquinazolinedihydrochloride The dihydrochloride is prepared by dissolving the basein hot ethanol and adding ethanolic hydrochloric acid solution toprecipitate the salt. M.P. 259260 C.

EXAMPLE XXXIX 2- N,N-diallylamino -4-a mine-6,7- dimethoxyquinazolineThe compound is prepared by the procedure of Example XXXVII usingdiallylamiue in ethanol rather than diethylarnine. The product melts177-179 C. The dihydrochloride salt, prepared as in Example XXVIII,melts 227-229 C.

EXAMPLE XL 2-amino-4- (N,N-dimethylamino) -6,7- dimethoxyquinazoline To80 grams of a 10% solution of dimethylamine in tetrahydrofuran at roomtemperature is added grams 2,4-dichloro-6,7-dimethoxyquinazoline. Themixture is stirred 48 hours. The resulting precipitate is filtered andrecrystallized from methanol. To 5 grams of the product is added 100.ml. of ethanolic ammonia. This mixture is heated at 160 C. for 16 hoursin a sealed pressure bottle. The solvent is evaporated and the residueis recrystallized from methanol/water.

EXAMPLE XLI 2-amino-4- (N,N-diarnylamino -6,7- diarnyloxyquinazoline To30 grams of 2,4-dichloro-6,7-diamyloxyquinazoline prepared as in ExampleTX, is added 80 grams of a 10% solution of diamyla-mine intetrahydrofuran. The mixture is stirred for 48 hours. The precipitatewhich forms is filtered and recrystallized from methanol. To 5 grams ofthe product is added 100 ml. ethanolic ammonia. This mixture is heatedat 160 C. for 16 hours in a sealed pressure bottle. The solvent isevaporated and the residue is recrystallized from methanol/water.

EXAMPLE XLII 2-4-di(N,N-dimethylarnino -6,7- dimethoxyquinazoline To 80grams of a 10% solution of dimethylamine in tetrahydrofuran at roomtemperature is added 30 grams 2,4-dichloro-6,7-dimethoxyquinazoline. Themixture is stirred 48 hours. The resulting precipitate is filtered andrecrystallized from methanol. To 5 grams of the product EXAMPLE XLIII2,4-di (N,N-diamy1amino) -6, 7 -dimethoxyquinazoline This compound isprepared with diamylarnine according to the procedure of Example XLII.

EXAMPLE XLIV 2,4-di(N,N-dimethylamiuo)-6,(7)-methoxyquinazoline Thesecompounds are prepared from 2,4-dichloro- 6-methoxyquinazoline (ExampleXIII) and 2,4-dichloro- 7-methoxyquinazoline (Example XIV) according tothe procedure of Example XLII.

EXAMPLE XLV 2-methylamino-4-amino-6,7-dimethoxyquinazoline This compoundis prepared by the procedure of Example XXXVII by reacting2-chloro-4-arnino-6,7- dimethoxyquinazoline with an ethanolic solutionof methylamine.

EXAMPLE XLVI 2-amylamino-4-amino-6,7-dimethoxyquinazoline This compoundis prepared by the procedure of Example XXXVII by reacting2-chloro-4-amino-6,7- dimethoxyquinazoline with an ethanolic solution ofamylamine.

EXAMPLE XLVII Z-N-ethylanilino-4-arnino-6,7-dimethoxyquinazoline Thiscompound is prepared by the procedure of Example XXXVII by reacting2-chloro-4-amin0-6,7- dimethoxyquinazoline With N-ethylaniline.

EXAMPLE XLVIII 2-N-methylbutylamino-4-amino-6,7-dimethoxyquinazolineThis compound is prepared by the procedure of Example XXXVII by reacting2-chloro-4-amino-6,7- dimethoxyquinazoline with N-methylbutylamine.

EXAMPLE XLIX Z-amino-4-N-methylbutylamino-6,7-dimethoxyquinazoline Thiscompound is prepared by the procedure of Example XL by reactingN-methylbutylamine with 2,4-dichloro-6,7-dimethoxyquinazoline.

EXAMPLE L The biological activity of the compounds of this invention,particularly in regard to their effectiveness in reducing blood pressurein hypertensive subjects, 'is illustrated by the following tests onrenal hypertensive dogs. The compounds were administered orally incapsule form. The effective dose level was that which lowered the bloodpressure from 180/100 to /100 mm. Hg. The activity of the compounds isshown in Table XVIII.

21 Table XVIII Hypotensive activity Minimum effective Compound:concentration, mg./kg. 2,4-diamino-6,7-dimethoxyquinazoline 2.50

2 methylamino 4 amino-6,7-dimethoxyquinazoline 2.50

2 ethylamino 4 amino-6,7-dimethoxyquinazoline 2.50

2 11 propylamino 4 amino-6,7-dimethoxyquinazoline 2.50

2 n butylamino 4 amino 6,7 dimethoxyquinazoline 2.50

2 isopropylamino 4 amino-6,7-dimethoxyquinazoline 1.25

2 dimethylamino 4 amino 6,7 dimethoxyquinazoline 0.63

2 diethylamino 4 amino-6,7-dimethoxyquinazoline 1.25 2 Nmethyl-(-hydroxyethyl)amino-4-amino- 6,7-dimethoxyquinazoline 2diallylamino 4 amino-6,7-dimethoxyquinazoline 2 (4 methyl 1piperazinyl)-4-amin0-6,7-dimethoxyquinazoline 2 5,5,5trifluoroethylamino 4 amino-6,7-dimethoxyquinazoline 2 (4 npropyl-l-piperazinyl)-4-amino-6,7-

dimethoxyquinazoline 2 (diethanolamino) 4-amino-6,7-dimethoxyquinazoline2 (dimethylamino) 4 methylamino-6,7-dimethoxyquinazoline 2.50 2,4di(diethylamino) 6,7 dimethoxyquinazoline 2,4 di(N,Ndimethylamino)-6,7-dimethoxyquinazoline EXAMPLE LI Tablets A tablet baseis prepared by blending the following ingredients in the proportion byweight indicated:

Sucrose, U.S.P. 80.3 Tapioca starch 13.2 Magnesium stearate 6.5

Into this base there is blended sufficient Z-dimethylamino-4-amino-6,7-dimethoxyquinazoline to provide tablets containing 20, 100and 250 mg. of active ingredient.

EXAMPLE LII Capsules A blend is prepared containing the followingingredients:

Calcium carbonate, U.S.P. 17.6 Dicalcium phosphate 18.8 Magnesiumtrisilicate, U.S.P 5.2 Lactone, U.S.P. 5.2 Potato starch 5.2 Magnesiumstearate A 0.8 Magnesium stearate B 0.35

mixture is filled into vials, sterilized with ethylene oxide and thevials sterilely stoppered. For intravenous administration sufiicientwater is added to the vials to form a solution containing 10 mg. ofactive ingredient per milliliter.

EXAMPLE LIV Suspension A suspension of 2-(N,N-diallylamino)-4-amino-6,7-dimethoxyquinazoline is prepared with the following composition:

Effective ingredient3l.42 g.

70% aqueous sorbitol714.29 g. Glycerine, U.S.P-185.35 g.

Gum acacia 10% solution)100.00 ml. Polyvinyl pyrrolidone0.5 g.

Water, distilled to make 1 liter.

To this suspension, various sweetening and flavoring agents may be addedby choice. The suspension contains approximately 25 mg. of hypotensiveagent per milliliter.

EXAMPLE LV Solution The solution has a concentration of rug/ml. and issuitable for parenteral and especially for intramuscular administration.

EXAMPLE LVI The methods employed for the preparation of the compounds ofthe previous examples are also used to prepare compounds havingsubstituents other than alkoxy on positions 5, 6, 7 and 8 of thequinazoline nucleus. These compounds are prepared from substitutedaromatic compounds such as those in Table XIX, followed by chlorinationas described in Examples VII, VIII, IX and X. These compounds are asfollows:

Table XIX Substituted 2,4dichloroquinazo1ines Starting compound:Substituents Methyl 5-chloroanthranilate 6-chloro-- 4-chloroanthranilicacid 7-chlor0- Methyl 3-bromoanthranilate 8-bromo- Methyl6-fluoroanthranilate S-fluoro- Methyl 4-fluoroanthranilate 7-fiuoro-4,S-dimethylanthranilamide 6,7-dimethyl- 5-pentylanthranilic acid6-pentyl Methyl 4-isopropylanthranilate 7-isopropyl- Methyl6-chloroanthranilate 5-chloro- Methyl 3-chloroanthranilate 8-chloro-Ethyl 3-fluoroanthranilate S-fiuoro- S-methylanthranilic acid 6-methyl-6-methylan thranilic acid S-methyl- 3-methylanthranilic acid S-methyl-S-nitroanthranilic acid 6-nitro- 6-nitroanthranilic acid S-nitro-3-amino-p-tolunitrile 7-methyl- 2-amino-4,5-dichlorobenzoic acid6,7-dichloro- 2-aminopiperonylic acid 6,7-methylenedioxy-2-amino-4,5-ethylenedioxybenzoic acid 6,7-ethylene-2-naphthylamine-3-carboxylic dioxyacid 6,7-benzo-4,5-dimethylanthranilic acid 6,7-dimethyl 4,5,6-trimethoxyanthranilicacid 5,6,7-trimethoxy These compounds are effective hypotensive agentswhose activities are similar to those in the previous examples. Inaddition, compounds selected from the group having the formula:

N Rs I W-Z R k) wherein R R and Z are as previously described are alsoefiective hypotensive agents. The compounds of this example are preparedaccording to the procedures of the preceding examples. They are used inthe same manner with regard to dosage level and dosage form as thecompounds in the previous examples. A specific example of thepreparation of this type of compound is as follows:

I Q'Hz Z-dimethylaminoi-amino-6,7-benzoquinazoline EXAMPLE LVII4-(4-amino-6,7-dimethoxyquinazoline-Z-yl)-piperazine-1- carboxylic acidisobutyl ester Preparation of isobutyl 1-piperazinecanboxylate.-To 11.6grams of anhydrous piperazine in 127 ml. ethanol and 16 ml. water isadded with stirring over a 30 minute period, 22.6 grams 48% aqueoushydrobromic acid. The temperature rises to 60 C. during the addition.Isobu-tyl chloroforrnate (875 grams) is then added over another 30minute period and the resulting solution is refluxed for 1.5 hours andchilled. The piperazine dihydrobromide which crystallizes is filteredand the solution is concentrated to an oil in vacuo. The oil is taken upin water, neutralized with dilute aqueous sodium hydroxide and extractedwith several portions of methylene chloride. The combined extracts aredried with sodium sulfate and the methylene chloride is evaporated toyield 9.9 grams of an oil which is distilled in vacuo, B.P. 87-90 C./0.3 mm. Hg pressure. The yield of colorless product is 7.17 grams or 60%of theory.

This same procedure is used to prepare 1-(2-furoyl)- piperazine, lallylpiperazine, 1 (2 methylallyl) piperazine, l crotonyl piperazine,propyl 1 piperazinecarboxylate, allyl 1 piperazinecarboxylate, and npentyl-l-piperazinecarboxylate.

Preparation of quinazoline derivative of isobutyl 1-piperazinecarboxylate.-A mixture of 7.17 grams of 2- chloro 4 amino 6,7dimethoxyquinazoline and 11.7 grams of isobutyl 1 piperazinecarboxylatein 80 ml. of ethanol is heated in a pressure bomb at 140 C. for 4 hours.The reaction mixture is cooled and the solvent evaporated. The resultingresidue is triturated with 300 ml. water. The insoluble material isfiltered from the Water and dissolved in 50 ml. methanol. The methanolis displaced with 50 ml. of ethyl acetate and the product isprecipitated and collected by filtration. The product is dissolved inwarm ethanol-1 N hydrochloric acid and chilled. The crystals of theresulting hydrochloride are filtered from the solvent and dried to yield8.1 grams of product (62% of theory) melting at 277278 C.

Analysis.--Calcd. for C H O N HCl /2H O (percent): C, 52.47; H, 6.72; N,16.12; Cl, 8.15. Found (percent): C, 52.69; H, 6.86; N, 16.23; Cl, 7.86.

EXAMPLE LVIII 2-(4-allyl-l-piperazinyl)-4-amino-6,7-

dimethoxyquinazoline To 18.9 grams of2-chloro-4-amino-6,7-dimethoxyquinazoline in 280 m1. of isoamyl alcoholis added 19.9 grams of l-allylpiperazine prepared as in Example LVII.The mixture is refluxed for 20 hours, and cooled. The l-allylpiperazinehydrochloride formed is extracted with water and the organic layer isconcentrated in vacuo to an oil which crystallizes when triturated withhexane. The solids are collected by filtration and dried to give 20.4grams of product, M.P. 198-201 C.

The hydrochloride salt is prepared by redissolving the product inethanol/1 N hydrochloric acid and chilling. The resulting crystals, whendried melt at 282-283 C.

EXAMPLE LIX 2-(4-benzylpiperidino) -4-amin'o-6,7-dimethoxyquinazoline To7.17 grams of 2-chloro-4-amino-6,7-dimethoxyquinazoline in ethanol isadded 10.5 grams 4-benzylpiperidine. The mixture is heated in a pressurebottle for 4 hours at C. The mixture is cooled, the solvent isevaporated and the residue is redissolved in methanolchloroform (1:1).This solvent is displaced with ethyl acetate causing crystallization ofproduct. The crystals collected weigh 6.8 grams, M.P. 260-262 C.

Analysis-Calm. for C H O N HCl (percent): C, 63.68; H, 6.56; N, 13.50;Cl, 8.55. Found (percent): C, 63.76; H, 6.58; N, 13.72; Cl, 8.43.

EXAMPLE LX 4-(4-amino-6,7-dimethoxyquinazoline-Z-yl) -piperazine-1-carboxylic acid ethyl ester hydrochloride This compound is prepared fromethyl l-piperazinecarboxylate and 2-chloro-4-amino-6,7-dimethoxyquinazoline according to the procedure of Example LVII.

Analysis.Calcd. for C H O N HCl fiH O (percent): C, 50.19; H, 6.19; N,17.22; Cl, 8.71. Found (percent): C, 49.78; H, 6.15; N, 17.11; Cl, 8.70.M.P. 277- 278 C.

EXAMPLE LXI 4- (4-amino-6,7-dimethoxyquinazoline-Z-yl)-piperazinel-carboxylic acid allyl ester hydrochloride This compound isprepared from allyl l-pi-perazinecarboxylate and2-chloro-4-amino-6,7-dimethoxyquinazoline according to the procedure ofExample LVII, The hydrochloride melts at 260262 C.

EXAMPLE LXII 2 [4- (p-hydroxyethyl) -piperidino-4-amino-6,7-dimethoxyquinazoliue hydrochloride This compound isprepared according to the procedure of Example XXDC from2-chloro-4-amino-6,7-dimethoxyquinazoline and1-p-hydroxyethylpiperidine. The hydrochloride salt is prepared accordingto the procedure of Example III. The compound melts at 239-240 C.

Analysis.Calcd. for C H O N HCl /2H O (percent): C, 54.04; H, 6.93; N,14.83; Cl, 9.38. Found (percent): C, 54.36; H, 7.11; N, 14.95; Cl, 9.22.

EXAMPLE LXIII 2-(4-n-propylpiperidino)-4-amino-6,7-dimethoxyquinazolinehydrochloride This compound is prepared from 2-chloro-4-amino-6,7-dimethoxyquinazoline and 4-n-propylpiperidine ac- 25 26 cording tothe procedures of Examples XXIX and III. TABLE XX The free base melts at150-151 C. The hydrochloride R R melts at 246-247 c. 3 Z

Analysis.Calcd. for C H O N (percent): C, 15- g pipergiilno 65.43; H,7.92; N, 16.95. Found (percent): C, 65.23; H, 5 gfgg gfii 7.90; N,16.84. CH CH gg-pentyl-l-piperiiilno i erazinyl- EXAMPLE LXIV C6H5 CH54-I rle l5hylearblamoy1-1- w y2-(4-n-heptanoyl-1-p1peraz1nyl)-4-am1no-6,7-d1methoxy- C6II5 CflH5 kcfthyl carblamoybb erazmy qulnazollne hydrochlonde CGHF CHF,iqigmpylcarbamoyLb This compound is prepared from 2-chloro-4-amin0-6,7-66H? ,.%$f, dimethoxyquinazoline and l-n-heptanoylpiperazine acp p ycording to the procedure of Examples XXIX and III. The %E igfiggggggggproduct melts at 155162 C. o%4- -g g sipipggg gg oH2 2- r CH 2-hex 1 ier ino EXAMPLE LXV 291 2 2 gierg y lp lpergilio a e 4-" y roxyme y- The2,4-d1substltuted-6,7-benzoqu1naz0lmes of the for piperldlno mu] 3-CH30CBH4 H- 4-hydroxymethylae plperldlno 2C(F)3CH- H- -acetyl-I-piperazinyl2-C(F)3CH2 H- 4-eaproyl-l-plpemzinyl 2-CuH13CuH H4-(2-iuroyl)-1-plperazinyl 4-FCtH4-- H- 4-(2-methylphenyD-1- plperazlnylC6H5- CcH5- 4-(g-trlfiufinimethyb I N enzoy -p1peraz1ny 2 I I EXAMPLELXVI \/\/N The 2,4-disubstituted 6(7)-methoxyquinazolines of theformulae: N N R3/ R. R l W N /R1 R5 N N 40 R R4 1 Z are prepared from2,4-dichloro-6,7-benzoquinazo1ine, as described in Example LVI, and bythe procedures of EX- amples XIX, XXII, XXIX, XXX, XXVIII and XXXV.

are prepared by the procedures of Examples XV, XVI, XIX, XXI, XXII,XXVIII and XXXV. These compounds EXAMPLE LXVII The biological activityof the compounds of this invention was tested according to the procedureof Example L. The activity of the compounds is given in Table XVIII ofExample L and Table XXII.

TABLE XXII.HYPOTENSIVE ACTIVITY N CH3O N N-R l NH:

Minimum Efieetive Concentration, R mgJkg.

E CHz=C-C H2- 1. 25

(I) CzH5O-C- 0. 075

(I? CHsCH-CHz-OC- 1.25

II CH:(IJH-CHT-OC' 0. 075

N 011,0 j N OH onto N Minimum Effective Concentration, s-1 g.

2-(4-hydroxy-1-piperidino)4-amino-6J-dimethoxyquinazoline 1. 25

EXAMPLE LXVIII Z-diethylamino-4-chloro-6,7-dimethoxyquinazoline Amixture of grams Z-diethyla-mino-6,7-dimethoxy- 4(3I-I)-quinazolenehydrochloride in 50 ml. of phosphorous oxychloride is refluxed for 2hours. The liquids are evaporated to give a crystalline residue of2-diethylamino-4-chloro 6,7 dimethoxyquinazoline hydrochloride, M.P.175184 C. The product is dissolved in dilute sodium hydrogen carbonateaqueous solution and is extracted several times with chloroform. Thecombined chloroform extracts are dried with sodium sulfate and thesolvent is evaporated to yield 7.6 grams (82% of theory) of product,M.P. 129-151" C.

Analysis.Calcd. for C I-I O H HCl. (percent): C, 56.86; H, 6.13; N,14.21. Found (percent): C, 56.81; H, 6.08; N, 13.97.

EXAMPLE LGX Z-diethylamino-Famine-6,7-dimeth0xyquinazoline2-(4-allyl-1-piperazinyl)-4-amino-6,7- dimethoxyquinazoline To 10 gramsof 6,7-din1ethoxy-(lH,3I-I)-quinazolinedione in 200 ml. pyridine isadded 30 grams phosphorous pentasulfide and the mixture is refluxed withcontinuous stirring for 5 hours. The solvent is removed under reducedpressure and the residue is decomposed with hot water. The solidmaterial is filtered from the mixture. The product is6,7-dimethoxy-(1H,3H) quinazolinedithione.

To 0.1 mole of 6,7-dimethoxy-(1H,3H)-quinazolinedithione in 220 ml. 1 Npotassium hydroxide solution and ml. methanol, is added slowly withstirring, 0.22 mole of methyl iodide. The mixture is heated on a steambath for 2 hours, cooled, and the resulting precipitate is filtered fromthe mixture. The product is2,4-dimethylmercapto-4-amino-6,7-dimethoxyquinazoline.

To 0.1 mole of 2,4-dimethylmercapto-6,7-dimethoxyquinazoline in 200 ml.of tetrahydrofuran is added a solution of 0.1 mole of anhydrous ammoniain tetrahydrofuran. The mixture is stirred at room temperature for 18hours and the precipitate which forms is collected and recrystallizedfrom dimethylformamide/water to yield 2-methylrnercapto-4-amino-6,7dimethoxyquinazoline.

A mixture of 0.1 mole of Z-methylmercapto-4-amino-6,7-dimethoxyquinazoline and 0.12 mole of l-allylpiperazine is isoamylalcohol is heated at reflux for 13 hours. The reaction mixture iscooled, washed with water, and the organic layer is concentrated invacuo. Hexane is slowly added to the oily residue and the solids whichform are collected. The product is 2-(4-allyl-l-piperazinyl)-4-amino 6,7dimethoxyquinazoline, MP. 198

EXAMPLE LXXI 30 EXAMPLE LXXV The 2,4-disubstituted 6,7 benzoquinazolinesof the formula:

2-(4-allyl-1-piperazinyl)-4-amino-6,7- N

dimethoxyquinazoline \T To 0.10 mole of 2-(1-piperazinyl) 4amino-6,7-di- I N methoxyquinazoline in 300 ml. of methanol at 50 C. isadded with vigorous stirring 0.10 mole allyl bromide. l The mixture isheated at reflux for 2 hours, cooled, and the crystalline material isfiltered. Recrystallization from ethanol yields the desired product. areprepared from 2,4-d1chloro-6,7-benzoqumazol1ne, as

described in Example LVI and by the procedures of EXAMPLE LXXII ExamplesXIX, XXII, XXIX, XXX, XXVHI and XXV.

These compounds are llsted in Table XXIV.2-[4-(2-furoyl)-piperazine-yl]-4-amino-6,7- TABLE XXIVdimethoxyquinazoline R1 R2 R3 R4 To 0.10 mole 2 (1 piperazinyl) 4amino-6,7-di- H H H- H-- methoxyquinazoline in 300 ml. methanol is addedwith 85g: EF a vigorous stirring, 0.10 mole 2-furoyl chloride. Afteraddi- OH3 H- CH CH3- tion is complete, the mixture is stirred for 3hours at 33%;; E: 2 6 5 1 room temperature. The solids are filtered togive the -Ca 7 p-Ca 1 n-C3H7 11-C3H7- desired product, M.P. 27s-2so c.EZ EE,= E:

sa eea; se

EXAMPLE LXXIII CH;C- :HZ c211; H ii:

2-diethy1amino-4-amino-6,7-dimethoxyquinazoline EZQIL%%ZJH2 g:IZQIGOLEHPCHF a 4 a s- H- To 0.1 mole 2-amino-4,5-dimethoxybenzonitrilein di- EEI g: 335 methylformamide is added 0.5 mole of N,N-diethyl- O2H5H 3-CH30O6H4- 05H;- guanidine. The mixture is heated for 12 hours at 150ggfia 5 ggfE- g C. The solution is concentrated to a small volume, in4-HOCE I4 H- H- H: vacuo. Water is added and the mixture is chilled. The35 CZHF UHF B'CHPCHP solids which crystallize are filtered from themixture EXAMPLE LXXVI and recrystallized from iso-propyl alcohol to givethe desimd product. The 2,4 disubstituted 6,7 dlmethoxyquinazolines ofTab e XXV are prepared according to the procedures of EXAMPLE LXXIV 40Examples I and XXXVII substituting the appropriate The 2,4 disubstituted6,7 alkylquinazolines of the amme for dlethylamme' formula: TABLE XXV R1N CH O N R2 R1 011 0 N R --N N I R /Ri H-N M.P., C.

R1 R2 Base 2.HC1

82 1 15 CH2CH2N(GH3)2 245447 239-240 where R and R are methyl, ethyl,n-propyl and iso- H; ci i ili i i iii "ilig" propyl and where Z is asindicated in Table XXIII, are Z B Wi M 35- 36 260- 6 prepared by theprocedures of Examples XV, XVI, XIX, CH3 gfijggggfigfiggigg @332 3223323XXI, XXII, XXVIII and XXXV. These compounds are H 2 zNHOHwHm 296 803-304mud in Table XXIII. H CH(CH3)CH2CH2CH2N(C2H5)2 185487 231-233 TABLEXXIII R1 01 R3 R2 01 R4 R5 R5 Z H H- H- CH3 cyclopropylamino- H H CH3-CH 4-crotonyl-l-piperaziny1- H- H CH3 H- 3-hydr0xyplperldino- H- CH3CzH5 H 3-methoxypiperidino- H- C2H5 C2H5- S-n-propoxypipeyldlno-Ifi-CaHzn-C;H1 OH; 3-n-butoxyp1per1d1non-O3H1- I1-C3H1-3-hydroxymethylpiperidino- CH; 11- 1so-C;H1- 1so-C;H1S-hydroxyhexylpiperidmo- $3. 55,- fizsa 8e51- at easter CH=CCH2 H3- CH3-CH;4 piperldino- CHE=CHCH2 CH2=CH-CHz CH3 OH;4-(3-iuroy1)-1-piperaziny1- CH2= CHCH2 CH2= CH-CHz- CH; CH;-4-crotonyl-l-piperazinyl- I 31 EXAMPLE xxvu The 2,4 disubstituted 6,7dimethoxyquinazolines of Table XXVI are prepared according to theprocedure of Examples XL, XLII and LXXX by substituting the appropriateamine.

EXAMPLE LXXVIII The biological activity of the compounds of thisinvention, particularly in regard to their effectiveness in reducingblood pressure in hypertensive subjects, is illustrated by the followingtests onrenal hypertensive dogs. The compounds were administered orallyin capsule form. The effective dose level was that which lowered theblood pressure from 180/ 100 to 160/100 mm. Hg. The

activity of the compounds is shown in Table XXVII.

TABLE XXVIL-HYPOTENSIVE ACTIVITY 1IH I EXAMPLE LXXIX2-furfurylamino-4-amino-6,7-dimethoxyquinazoline 32 EXAMPLE LXXX Thecompounds of Table XXVHI are prepared by the procedure of ExampleXXXVII. Substituting the appropriate amine for diethylamine'.

TABLE XXVIII EXAMPLE LXXXI The compounds of Table XXIX are preparedaccording to the procedures of Examples XL, XLII, LXXIX and LXXX.

TABLE XXIX R R2 R3 R4 H H 2-Iuriuryl H H H 2-iurfuryl CH H H 2-theny1 HH H (2-thicnyl) ethyl 0 H 2turiuryl H Z-iurfuryl 0 H Z-thenyl 0 H32-furiuryl H z-thienyl H Z-theuyl C H (ZJuryl) ethyl H 2theny1 H EXAMPLELXXXII The compounds of Table XXX are prepared accord- 33 ing to theprocedures of Examples XXII, XXX, XXIX, and LXXXI.

R1 N N 011311 2 onto -N 2 01130 N onto N l l N Z Ra R4 2-furiuryl Hmorpholino 2-thenyl H piperazino (2-furyl)ethyl H morpholmo(Z-thienyDethyl H phenyl 2-Iurfuryl H 4-phenylp1per1diono EXAMPLELXXXIII The compounds of Table XXXI are prepared by the procedures ofExamples LXXII and LVII substituting the chloride indicated.

TABLE XXXI Chloride Product 34 EXAMPLE LXXXIV 2-chloro-4-(Z-hydroxyethylamino -6,7-dimethoxyquinazoline 1 To 150 ml. oftetrahydrofuran was added 7.75 grams 2,4-dichloro-6,7-dimethoxyquinazoline. To the stirred solution was added atroom temperature, 5.38 ml. of 2- aminoethanol. The resulting suspensionwas stirred for 2 hours at room temperature and filtered to give 9.6grams of the hydrochloride salt of2-chloro-4-(2-hydroxyetliylamino)-6,7-dimethoxyquinazoline, M.P. 2l02 13C.

The free base was prepared by suspending the hydrochloride in an aqueoussolution of sodium bicarbonate for 1 hour. The product, 7.25 grams(85.3% of theory) melted 249-251 C.

EXAMPLE LXXXV 2- [4- (Z-furoyl -piperazinl-yl] -4- (2-hydroxyethylamino)-6,7-dimethoxyquinazoline 2- [4-(2-furoyl) -1'-piperazinyl]-4-diacetylamino- 6,7-dimethoxyquinazoline A suspension of 9.12 grams(23.8 mmoles) of 2-[4- (2 furoyl)l-piperazinyl]-4-amino-6,7-dimethoxyquinazoline, 175 ml. of pyridine and175 ml. (189 grams, 1.848 moles) of acetic anhydride was heated on astream cone to give a solution. The solution was stirred at roomtemperature for 16 hours and concentrated in vacuo to a crystallineresidue. Recrystallization from ethyl alcoholwater gave 8.3 grams (78%of theory) of product, M.P. 230-233 C.

Analysis.-For C23H250N5 Calcd. (percent): C, 59.09; H, 5.39; N, 14.98.Found (percent): C, 59.26; H, 5.49; N, 15.10.

EXAMPLE LXXXVII 2-diethylamino-4-acetamino-6,7-dimethoxyquinazoline To asolution of 3.2 grams 2-diethylamino-4-amino- 6,7-dimethoxyquinazolinein 25 ml. pyridine was added 25 ml. (0.264 mole) of acetic anhydride.The mixture was stirred at room temperature for 2 hours and concentratedin vacuo to a crystalline residue. Recrystallization from ethylalcohol-water gave 3.0 grams (82% of theory) of the pure product, M.P.237239 C.

Analysis.F0r C H O N Calcd. (percent): C, 60.36; H, 6.97; N, 17.60.Found (percent): C, 60.71; H, 6.82; N, 17.70.

EXAMPLE LXXXVIII 2-diethylamino-4-[ (3 -diethylamino propyl) amino]6,7-dimethoxyquinazoline To a suspension of 6.0 grams2-diethylamino-4-chloro 6,7-dimethoxyquinazoline hydrochloride in 50 ml.tetrahydrofuran was added 5.62 grams 3-dimethylaminopropylamine. Theresulting mixture was refluxed for 48 hours. The solution wasconcentrated to an oil in vacuo. Crystallization from methyl alcoholwater gave 3.7 grams (51.5% of theory) of product, M.P. 107-109" C.

Analysis.--For C H O N +%H O. Calcd.

35 (percent): C, 63.29; H, 9.06; N, 17.57. Found (percent): C, 63.28; H,8.94; N, 17.29.

EXAMPLE LXXXIX 2-[4-(4-phenyl-4 -carboxylic acid ethylester)-1-piperidino] -4-amino-6,7 -dimethoxyquinazoline2-(4-propargyl-l-piperazinyl) -4-amino-6,7

dimethoxyquinazoline 0. 62 2-[i-(2benzofuroyl)-1-piperazinyl1-4-amin0-6,?-

dimethozyquinazoline 10 2-{4-(4-phenyl4-carboxylic acid ethyl ester) -1-piperidino]-4-amino-6,7-dimethoxyqu1nazoline 1. 25 2-[4-(3-pyridinylcarbonyl) -1-piperazinyl]-4-amino- 6,7-dimethoxyquinazoline 0. 3

' ethylarnino-4-acety1amino-6J- 2-dhnethoxyqulnazo1ine 1 2-(4-a11y-1-piperaziuyl) -4-acety1ammo-6,7-

dimethoxyquinazoline 1 2-(4: [uroyl-l-piperazinyl) -4-diacetylamino-fi7- dimethoxyquinazoline 2.

EXAMPLE XCII The 2,4 disubstituted 6,7 dimethoxyquinazolines in Table}O(XIV were given orally to dogs at the levels shown. The resultingdecrease in blood pressure is indi- ,cated.

TABLE XXXIV Compound N CHaO I w-R N CH O Blood Pressure Lowering, Dose,R mm. Hg mgJkg.

4-(3-chlorophenyl) -1-piperaziny1 25 1. 25 4-(2-hydroxyethyl)-1-pipdrazinyl 20 10. O 4-(3-hydroxypropyD-1-piperazinyL 20 10. 04-(2-thenoyl)-1-piperazinyl 22 l. 25 Z-morpholinoethylamino 15 10. 0

N omof R 011.0-

l H CH Diethylamino 4O A-benzoyld-piperazinyl 3O 1. 25Q-allyl-l-piperazinyl 20 1. 25

N cmo- -R N CHSO 1 NH 0 H2 C H2 0 H 4 -iuroyl-l-piperaziny1 3O 25. 1

36 EXAMPLE XCIII The biological activity of the compounds of Table XXXVwas tested according to the procedure of Example LXXVIII.

5 TABLE XXXV Compound cH.ow-a 10 CH N Minimum effective R conc. (mg/kg.)Azacyclooctyl 10.0 Azacyclohexyl 10.0 4-m'ethylpiperidino 10.04-n-propylpiperidino 0.31 41'benzy1piperidino 0.31 4-phenylpiperidino1.25 Morpholino 10.0- Cyclopropylarnino 1.25 Benzylamino 10.04-butanoyl-1-piperazinyl 0.31 4-phenyI-1-piperazinyl 1.254-benzyl-1-piperaziny1 10.0 4-(3-chlorobenzoyl)-1-piperazinyl 10.04-(2-chlorobenzoyl)-1-piperazinyl 10.0 4-(3-methylbenzoyl)1-piperazinyl1.25 4- 3 ,4,5-trimethoxybenzoyl) -1-piperaziny1 10.04-(3-trifluoromethylbenzoyl)-l-piperazinyl 10.0

What is claimed is: 1. A compound selected from the group consisting ofthose having the formula:

N R1 R. N

' R2 R5 \/N where:

R llT-( GH3 where R is hydrogen, acetyl, alkyl having from 1 to 5 carbonatoms and alkenyl having from 3 to 5 carbon atoms; and piperazino of theformula:

where Y is hydrogen, alkyl having from 1 to 5 carbon atoms, hydroxyalkylwhere alkyl has from 2 to 5 carbon atoms, alkanoyl having from 2 to 7carbon atoms, allyl, propargyl, 2-methylally1, phenyl, benzyl, benzoyl,halobenzoyl and halo phenyl where halo is chloro or brorno,trifluoromethyl, methoxyphenyl, methylphenyl, methylbenzoyl,methoxybenzoyl, trifluoromethylben- 'zoyl, furoyl, benzofuroyl, thenoyl,pyridinecarbonyl, 3,4,5 trimethoxybenzoyl, carboxylic acid alkyl esterWhere alkyl has from 1 to 6 carbon atoms, carboxylic acid alkenyl esterwhere alkenyl has from 3 to 6 carbon atoms;

piperadino of the formula:

where X is hydrogen, alkyl having from 1 to carbon atoms, alkoxy havingfrom 1 to 4 carbon atoms, hydroxy, hydroxyalkyl where alkyl has from 2to 5 carbon atoms, phenyl, benzyl, 4-phenyl-4-carboxylic acid alkylester where alkyl has from 1 to 6 carbon atoms;

R and R are each selected from hydrogen and alkoxy having from 1 to 3carbon atoms, at least one of R and R being alkoxy; and the acidaddition salts thereof.

- 2. A compound selected from the group consisting of those having theformula:

where:

R; and R are each selected from hydrogen, alkyl having from 1 to 5carbon atoms, alkenyl having from 3 to 5 carbon atoms, hydroxyalkylhaving from 2 to 5 carbon atoms, phenyl, benzyl, phenylethyl,2-furfuryl, 2,2,2- trifiuoroethyl and cycloalkyl where alkyl has from 3to 8 carbon atoms;

Z is selected from morpholino l azacycloheptyl, l-azacyclooctyl andacetylamino of the formula:

allyl, propargyl, 2-methylallyl, phenyl, benzyl, benzoyl, halobenzoyland halophenyl where halo is chloro or :bromo, trifluoromethyl,methoxyphenyl, methylphenyl, methylbenzoyl, methoxybenzoyl,trifluoromethylbenzoyl, furoyl, benzofuroyl, thenoyl, pyridinecarbonyl,3,4,5-trimethoxybenzoyl, carboxylic acid alkyl ester where alkyl hasfrom 1 to 6 carbon atoms, carboxylic acid alkenyl ester where alkenylhas from 3 to 6 carbon atoms; and piperidino of the formula:

where X is hydrogen, alkyl having from 1 to 5 carbon atoms, alkoxyhaving from 1 to 4 carbon atoms, hy-

droxy, hydroxyalkyl where alkyl has from 2 to 5 carbon atoms, phenyl,benzyl, 4-phenyl-4-carboxylic acid alkyl ester where alkyl has from 1 to6 carbon atoms; and

R and R are each selected from hydrogen, and alkoxy having from 1 to 3carbon atoms, at least one of R and R being alkoxy; and the acidaddition salts thereof.

3. 2 [4 (2 furoyl)'- 1 piperazine 1 yl] 4-amino-6,7-dimethoxyquinazoline.

4. 2 (4 allyl 1 piperazinyl)-amino-6,7-dimethoxyquinazoline.

5. 2 [4 (2 methylallyl) 1 piperazinyl] 4-amino-6,7-dimethoxyquinazoline.

6, 2 (4 benzoyl 1 piperazinyl) 4 amino-6,7-dimethoxyquinazoline.

7. 4 (4 amino 6,7 dimethoxyquinazoline 2 yl) piperazine 1 carboxylicacid isobutyl ester.

U.S. Cl. X.R. 260247.5, 251, 256.5; 424200, 251

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. r3 D td May 12, 1970 Inve t-Grog) Hans-Jurgen E. Hess It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Col. 1, line 25, "August 6, 1965" should read -July 6, 1965-- Signcd andScaled this Sixteenth Day of August I983 |SEAL| Amsl:

GERALD I. MOSSINGHOFF Allesllng Officer Commissioner of Parents andTrademarks

